Using the Summit supercomputer at the Department of Energy's Oak Ridge National Laboratory, researchers have modeled a key component of nucleotide excision repair (NER) called the pre-incision complex (PInC), which plays a crucial role in DNA damage repair. Their study, published in Nature Communications, provides new insights into how the PInC machinery orchestrates precise DNA excision, potentially leading to advancements in treating genetic disorders, preventing premature aging, and understanding conditions like xeroderma pigmentosum and Cockayne syndrome. Phys.Org reports: "Computationally, once you assemble the PInC, molecular dynamics simulations of the complex become relatively straightforward, especially on large supercomputers like Summit," [said lead investigator Ivaylo Ivanov, a chemistry professor at Georgia State University]. Nanoscale Molecular Dynamics, or NAMD, is a molecular dynamics code specifically designed for supercomputers and is used to simulate the movements and interactions of large biomolecular systems that contain millions of atoms. Using NAMD, the research team ran extensive simulations. The number-crunching power of the 200-petaflop Summit supercomputer -- capable of performing 200,000 trillion calculations per second -- was essential in unraveling the functional dynamics of the PInC complex on a timescale of microseconds. "The simulations showed us a lot about the complex nature of the PInC machinery. It showed us how these different components move together as modules and the subdivision of this complex into dynamic communities, which form the moving parts of this machine," Ivanov said.

The findings are significant in that mutations in XPF and XPG can lead to severe human genetic disorders. They include xeroderma pigmentosum, which is a condition that makes people more susceptible to skin cancer, and Cockayne syndrome, which can affect human growth and development, lead to impaired hearing and vision, and speed up the aging process. "Simulations allow us to zero in on these important regions because mutations that interfere with the function of the NER complex often occur at community interfaces, which are the most dynamic regions of the machine," Ivanov said. "Now we have a much better understanding of how and from where these disorders manifest."

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